Novel anti-hypertensive compositions

ABSTRACT

Novel pharmaceutical compositions are disclosed which comprise a hypotensive agent and a phenyl hydrazino substituted propionic acid decarboxylase inhibitor. The compositions have enhanced anti-hypertensive activity.

This is a division of application Ser. No. 657,825, filed Feb. 13, 1976, now U.S. Pat. No. 4,055,645.

BACKGROUND OF THE INVENTION

The present invention is directed to novel pharmaceutical compositions containing a hypotensive agent and a decarboxylase inhibitor.

The hypotensive agents of the present invention comprise agents, other than phenylalanine and reserpine type compounds, which are known to be effective in treating hypertension in humans. The decarboxylase inhibitor is encompassed in the class of hydrazino phenyl propionic acid compounds disclosed in U.S. Pat. No. 3,462,536; U.S. Pat. No. 3,830,827 and U.S. Pat. No. 3,781,415. Combinations of this hydrazino phenylpropionic acid type decarboxylase inhibitor with reserpine or phenylalanine type hypertensive agents are disclosed in Canadian Pat. No. 737,907 and U.S. Pat. No. 3,839,585.

It has now been discovered that the combination of the aforesaid non-phenylalanine, non-reserpine hypotensive agents with the hydrazino-phenyl propionic acid type decarboxylase inhibitors affords enhanced anti-hypertensive activity.

SUMMARY OF THE INVENTION

Novel pharmaceutical compositions comprising (a) a non-phenylalanine, non-reserpine hypotensive agent and (b) a D,L- or L-hydrazino-phenyl propionic acid decarboxylase inhibitor and a method of treating hypertensive animals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of this invention is a hypotensive pharmaceutical composition comprising

(A) A NON-PHENYLALANINE, NON-RESERPINE HYPOTENSIVE AGENT AND

(B) THE L-isomer or racemic mixture (D,L-) of a hydrazino phenylpropionic acid decarboxylase inhibitor.

Preferred hypotensive agents are selected from the group consisting of (1) spironolacetone, hydralazine, trimethaphan camsylate, clonidine, quanethidine, thiazide diuretics, cryptenamine, pharmaceutically acceptable salts thereof and (2) sodium nitroprusside. A more preferred group of hypotensive agents includes hydralazine, clonidine, guanethidine, the thiazide diuretics and pharmaceutically acceptable salts thereof. A most preferred group of hypotensive agents is clonidine, hydralazine, guanethidine and their pharmaceutically acceptable salts.

The thiazide diuretics include the benzothiadiazine class of compounds having the basic ring structure ##STR1## Representative compounds are disclosed in U.S. Pat. No. 2,809,184; U.S. Pat. No. 2,937,169; U.S. Pat. No. 3,025,292; U.S. Pat. No. 3,164,588 and U.S. Pat. No. 3,043,840, and are incorporated herein by references.

The preferred thiazide compounds are chlorothiazide, hydrochlorothiazide, trichlormethiazide, bendroflumethiazide, polythiazide, flumethiazide, and their pharmaceutically acceptable salts. Hydrochlorothiazide is a most preferred thiazide hypotensive agent.

Preferred decarboxylase inhibitors include the D,L-racemic mixture and the individual L-isomer of compounds having the formula: ##STR2## wherein R, R₁, R₂ and R₃ are independently selected from hydrogen and C₁ -C₄ alkyl such as methyl, t-butyl, isopropyl and the like. A more preferred decarboxylase inhibitor is the L-isomer and most preferred is the L-isomer of ##STR3## and its pharmaceutically acceptable salts. The monohydrate of IV is known as carbidopa.

Pharmaceutically acceptable salts include the salts of the various compounds with suitable organic or inorganic acids. Suitable organic acids are C₂ -C₂₄ carboxylic acids such as acetic acid, maleic acid, pamoic acid, succinic acid, citric acid, propionic acid, isethionic acid, oxalic acid, pivalic acid and the like. Suitable inorganic acids include the hydrohalides, e.g. HCl, HI, HBr, sulfuric acid, phosphoric acid and the like. The salts may also be alkali metal salts such as the sodium or potassium salt or the ammonium salt.

The compositions of the present invention may contain varying amounts of the hypotensive agent and decarboxylase inhibitor. In general, the weight ratio of hypotensive agent (a) to decarboxylase inhibitor (b) will be from about 4:1 to about 1:9000. A preferred weight ratio of (a): (b) is about 1:1 to about 1:1000 and a most preferred weight ratio is about 1:5 to about 1:500.

In treating hypertension, a sufficient amount of the present composition is administered to the hypertensive animal to produce the desired hypotensive effect i.e. reduction in blood pressure. Effective dosages may vary and can range from about 0.2 mg/kg to about 1000 mg/kg per day. The composition may be given as a single daily dose or divided into several smaller doses during the course of the day.

The composition may be administered parenterally or orally. The dosage form used will depend on the mode of administration. The oral form may be a tablet, a liquid solution, dispersion, or emulsion, a capsule, or an encapsulated composition -- while the parenteral dosage form will generally be a liquid solution, suspension or emulsion. The dosage forms generally will include conventional carriers, diluents, either solid or liquid, dyes etc. and will be prepared using applicable formulation procedures.

The compositions of the present invention are administered to hypertensive animals to effect reduction in blood pressure. The decarboxylase inhibitors are known to have no appreciable anti-hypertensive effect. When combined with the present hypotensive agents, however, the anti-hypertensive effect of the hypotensive agent is unexpectedly enhanced.

This enhancement of anti-hypertensive activity is demonstrated in vivo in spontaneously hypertensive (SH) rats. The procedure used is as follows:

The test animals used were conscious, male, SH rats weighing about 290 to about 340 grams. The arterial blood pressure was measured by a direct technique involving cannulation of the caudal artery. Initial blood pressure reading was recorded. The decarboxylase inhibitor was then administered intraperitoneally (i.p.) and about 5 minutes later the hypotensive agent was given, (i.p.). The blood pressure was then continuously recorded at 1/2 hour intervals for 24 hours.

The effect on blood pressure of the decarboxylase inhibitor and the hypotensive agent alone was also obtained by this method. The results of these tests for representative compositions of the present invention are in the following tables:

                                      Table 1                                      __________________________________________________________________________     Effects of guanethidine and hydrochlorothiazide, alone and in combination      with carbidopa, on the                                                         mean arterial pressure of conscious SH rats.                                                   Dose     Mean Arterial Pressure, mm Hg,                        Group           mg/kg                                                                               No. of                                                                             at hours after treatment                              No. Treatment   i.p. Rats                                                                               0  1/2                                                                               1  2  4  8  12 18 24                            __________________________________________________________________________     1   Saline      2 ml/kg                                                                             9   168                                                                               170                                                                               170                                                                               170                                                                               166                                                                               164                                                                               166                                                                               166                                                                               164                           2   Carbidopa.sup.1                                                                            25   6   167                                                                               166                                                                               164                                                                               166                                                                               158                                                                               167                                                                               172                                                                               172                                                                               162                           3   Guanethidine.sup.2                                                                         0.078                                                                               6   179                                                                               178                                                                               177                                                                               177                                                                               174                                                                               180                                                                               180                                                                               177                                                                               178                           4   Guanethidine                                                                               0.312                                                                               5   174                                                                               167                                                                               168                                                                               171                                                                               171                                                                               174                                                                               170                                                                               170                                                                               166                           5   Guanethidine                                                                               0.625                                                                               4   176                                                                               180                                                                               180                                                                               178                                                                               172                                                                               179                                                                               173                                                                               174                                                                               176                           6   Guanethidine                                                                               1.25 4   171                                                                               143                                                                               163                                                                               150                                                                               150                                                                               154                                                                               147                                                                               155                                                                               162                           7   Guanethidine                                                                               5    4   174                                                                               131                                                                               133                                                                               132                                                                               140                                                                               157                                                                               155                                                                               163                                                                               162                           8   Carbidopa & 25   4   173                                                                               161                                                                               162                                                                               173                                                                               166                                                                               172                                                                               171                                                                               172                                                                               170                               Guanethidine                                                                               0.312                                                          9   Carbidopa & 25   6   173                                                                               157                                                                               140                                                                               137                                                                               137                                                                               144                                                                               152                                                                               147                                                                               149                               Guanethidine                                                                               0.625                                                          10  Carbidopa & 25   4   166                                                                               126                                                                               133                                                                               129                                                                               126                                                                               141                                                                               147                                                                               158                                                                               157                               Guanethidine                                                                               1.25                                                           11  Hydrochlorothiazide.sup.3                                                                  5    4   170                                                                               179                                                                               177                                                                               176                                                                               165                                                                               170                                                                               174                                                                               171                                                                               171                           12  Hydrochlorothiazide                                                                        20   4   164                                                                               161                                                                               159                                                                               161                                                                               159                                                                               163                                                                               152                                                                               151                                                                               149                           13  Hydrochlorothiazide                                                                        40   5   168                                                                               167                                                                               167                                                                               164                                                                               163                                                                               161                                                                               159                                                                               155                                                                               155                           14  Hydrochlorothiazide                                                                        80   5   169                                                                               152                                                                               160                                                                               142                                                                               145                                                                               145                                                                               141                                                                               141                                                                               140                           15  Carbidopa & 25   4   170                                                                               169                                                                               161                                                                               159                                                                               156                                                                               158                                                                               152                                                                               154                                                                               152                               Hydrochlorothiazide                                                                        5                                                              16  Carbidopa & 25   4   170                                                                               164                                                                               164                                                                               163                                                                               155                                                                               162                                                                               158                                                                               158                                                                               153                               Hydrochlorothiazide                                                                        20                                                             17  Carbidopa & 25   5   179                                                                               181                                                                               170                                                                               162                                                                               148                                                                               160                                                                               158                                                                               162                                                                               161                               Hydrochlorothiazide                                                                        40                                                             18  Carbidopa & 25   6   176                                                                               153                                                                               146                                                                               146                                                                               128                                                                               135                                                                               133                                                                               138                                                                               146                               Hydrochlorothiazide                                                                        80                                                             __________________________________________________________________________      .sup.1 Dissolved in 1N HCl                                                     .sup.2 As Guanethidine sulfate dissolved in water                              .sup.3 Dissolved in 1N NaOH                                              

                                      Table 2                                      __________________________________________________________________________     Effect of hydralazine and clonidine, alone and in combination with             carbidopa, on the mean arterial                                                pressure of conscious SH rats.                                                             Dose        Mean Arterial Pressure, mm Hg,                         Group       mg/kg   No.of                                                                              at hours after treatment                               No. Treatment                                                                              i.p.    Rats                                                                               0  1/2                                                                               1  2  4  8  12 18 24                             __________________________________________________________________________     1   Saline  2 ml/kg 9   168                                                                               170                                                                               170                                                                               170                                                                               166                                                                               164                                                                               166                                                                               166                                                                               164                            2   Carbidopa.sup.1                                                                        25      6   167                                                                               166                                                                               164                                                                               166                                                                               158                                                                               167                                                                               172                                                                               172                                                                               162                            3   Hydralazine.sup.2                                                                      0.03    3   167                                                                               169                                                                               165                                                                               173                                                                               172                                                                               166                                                                               168                                                                               171                                                                               173                            4   Hydralazine                                                                            0.125   4   170                                                                               166                                                                               165                                                                               166                                                                               171                                                                               174                                                                               168                                                                               168                                                                               167                            5   Hydralazine                                                                            0.25    4   180                                                                               159                                                                               166                                                                               172                                                                               170                                                                               172                                                                               175                                                                               176                                                                               169                            6   Hydralazine                                                                            0.5     9   164                                                                               128                                                                               138                                                                               146                                                                               152                                                                               161                                                                               160                                                                               160                                                                               159                            7   Hydralazine                                                                            1       4   180                                                                               120                                                                               127                                                                               157                                                                               157                                                                               178                                                                               176                                                                               177                                                                               176                            8   Hydralazine                                                                            2       5   169                                                                               120                                                                               126                                                                               135                                                                               144                                                                               152                                                                               156                                                                               154                                                                               162                            9   Carbidopa &                                                                            0.312   4   166                                                                               158                                                                               146                                                                               154                                                                               153                                                                               166                                                                               164                                                                               163                                                                               157                                Hydralazine                                                                            0.125                                                              10  Carbidopa &                                                                            1.25    4   163                                                                               155                                                                               142                                                                               145                                                                               151                                                                               156                                                                               147                                                                               147                                                                               151                                Hydralazine                                                                            0.125                                                              11  Carbidopa &                                                                            5       4   168                                                                               187                                                                               175                                                                               166                                                                               163                                                                               135                                                                               133                                                                               130                                                                               152                                Hydralazine                                                                            0.125                                                              12  Carbidopa &                                                                            25      4   174                                                                               163                                                                               157                                                                               144                                                                               138                                                                               152                                                                               160                                                                               163                                                                               160                                Hydralazine                                                                            0.03                                                               13  Carbidopa &                                                                            25      5   177                                                                               137                                                                               132                                                                               149                                                                               140                                                                               149                                                                               151                                                                               155                                                                               158                                Hydralazine                                                                            0.125                                                              14  Carbidopa &                                                                            25      4   173                                                                               146                                                                               147                                                                               158                                                                               158                                                                               159                                                                               164                                                                               164                                                                               170                                Hydralazine                                                                            0.25                                                               15  Carbidopa &                                                                            1.25    6   169                                                                               143                                                                               149                                                                               156                                                                               159                                                                               161                                                                               157                                                                               165                                                                               166                                Hydralazine                                                                            0.5                                                                16  Carbidopa &                                                                            5       6   172                                                                               134                                                                               129                                                                               143                                                                               150                                                                               152                                                                               152                                                                               149                                                                               154                                Hydralazine                                                                            0.5                                                                17  Carbidopa &                                                                            25      8   175                                                                               117                                                                               115                                                                               130                                                                               141                                                                               149                                                                               153                                                                               153                                                                               153                                Hydralazine                                                                            0.5                                                                18  Clonidine.sup.3                                                                        0.00075 4   170                                                                               171                                                                               171                                                                               170                                                                               169                                                                               166                                                                               172                                                                               161                                                                               170                            19  Clonidine                                                                              0.003   4   169                                                                               166                                                                               156                                                                               165                                                                               163                                                                               165                                                                               168                                                                               177                                                                               179                            20  Clonidine                                                                              0.0125  4   167                                                                               159                                                                               167                                                                               163                                                                               163                                                                               169                                                                               169                                                                               167                                                                               172                            21  Clonidine                                                                              0.025   6   168                                                                               148                                                                               147                                                                               149                                                                               151                                                                               154                                                                               151                                                                               149                                                                               150                            22  Clonidine                                                                              0.05    7   180                                                                               164                                                                               159                                                                               149                                                                               146                                                                               154                                                                               159                                                                               164                                                                               166                            23  Clonidine                                                                              0.2     3   173                                                                               164                                                                               147                                                                               152                                                                               150                                                                               148                                                                               152                                                                               157                                                                               162                            24  Carbidopa &                                                                            25      6   169                                                                               153                                                                               157                                                                               158                                                                               162                                                                               175                                                                               169                                                                               163                                                                               171                                Clonidine                                                                              0.00075                                                            25  Carbidopa &                                                                            25      6   168                                                                               134                                                                               141                                                                               146                                                                               150                                                                               148                                                                               151                                                                               152                                                                               162                                Clonidine                                                                              0.003                                                              26  Carbidopa &                                                                            25      5   166                                                                               144                                                                               139                                                                               143                                                                               154                                                                               161                                                                               167                                                                               170                                                                               164                            27  Carbidopa &                                                                            25      4   170                                                                               149                                                                               121                                                                               114                                                                               116                                                                               127                                                                               135                                                                               136                                                                               42                             28  Carbidopa &                                                                            1.25    4   180                                                                               156                                                                               149                                                                               148                                                                               151                                                                               159                                                                               171                                                                               170                                                                               175                                Clonidine                                                                              0.05                                                               29  Carbidopa &                                                                            5       5   175                                                                               142                                                                               129                                                                               128                                                                               132                                                                               149                                                                               153                                                                               156                                                                               164                                Clonidine                                                                              0.05                                                               __________________________________________________________________________      .sup.1 Dissolved in 1N HCl                                                     .sup.2 As hydralazine . HCl Dissolved in water                                 .sup.3 As clonidine . HCl Dissolved in HCl                               

The above data clearly shows the enhancement of anti-hypertensive properties of the non-reserpine, non-phenylalanine agent by the decarboxylase inhibitor.

Following are formulations of some representative dosage forms:

    ______________________________________                                         Tablet Formulation                                                             Clonidine hydrochloride                                                                               0.1     mg                                              Carbidopa              5.0     mg                                              Calcium phosphate      50.0    mg                                              Lactose                20.0    mg                                              Starch                 10.0    mg                                              Magnesium sulfate      0.5     mg                                              Liquid Suspension                                                              Guanethidine sulfate   2.5     g                                               Carbidopa              2.5     g                                               Veegum HV              3.0     g                                               Methylparaben          1.0     g                                               Kaolin                 10.0    g                                               Glycerin               250.0   g                                               Water, q.s. → 1 liter                                                   Injectable Solution                                                            Hydralazine hydrochloride                                                                             20      mg                                              Carbidopa .HCl         100     mg                                              Distilled water, q.s. → 1 ml                                            Capsule Formulation - I                                                        Hydrochlorothiazide    50      mg                                              Carbidopa              15      mg                                              Lactose                50      mg                                              Talc                   3       mg                                              Capsule Formulation - II                                                       Clonidine HCl          0.2     mg                                              Carbidopa              100.0   mg                                              Mannitol               98.0    mg                                              Stearic acid           1.0     mg                                              ______________________________________                                    

While the test results were obtained by i.p. administration of the two drugs of the present composition separately, the effect is demonstrative of the anti-hypertensive effect which would be obtained on administration, orally or parenterally, of the hypotensive agent and decarboxylase inhibitor either as a combination or individually and simultaneously. Another embodiment of this invention is a method of treating hypertensive animals by thus administering an anti-hypertensive amount of the aforesaid composition comprising the hypotensive agent and the decarboxylase inhibitor.

The term animals includes humans.

Claims to the invention follow. 

What is claimed is:
 1. A pharmaceutical composition for treating hypertension comprising(a) a hypotensive agent selected from trimethaphan camsylate, clonidine and pharmaceutically acceptable salts thereof and (b) racemic mixture or L-isomer of a hydrazino phenyl propionic acid decarboxylase inhibitor, in an effective amount.
 2. The pharmaceutical composition of claim 1 whereinsaid decarboxylase inhibitor has the formula: ##STR4## wherein R, R₁, R₂ and R₃ are independently selected from hydrogen and C₁ -C₄ -alkyl, and pharmaceutically acceptable salts thereof.
 3. The composition of claim 2 wherein R, R₂, and R₃ are hydrogen and R₁ is methyl and said (b) inhibitor is the L-isomer, substantially free of the D-isomer.
 4. The composition of claim 3 wherein said hypotensive agent is clonidine or salt thereof.
 5. The composition of claim 2 wherein said hypotensive agent is trimethaphan camsylate.
 6. A method for treating hypertensive animals which comprises administration of an anti-hypertensive amount of the claim 1 composition. 